Computational Studies of Histone Modifications

描述(申请人提供)：我们的长期目标是开发和应用计算方法，为组蛋白修饰酶的催化和调节提供新的机制见解，并促进合理设计用于探索表观遗传途径和治疗用途的酶亚型特定调节剂。可逆组蛋白乙酰化在许多必要的表观遗传过程中已成为一个重要的调节因子。负责这种重要的翻译后修饰的酶是组蛋白乙酰转移酶(HATS)和组蛋白去乙酰基酶(HDAC)，它们分别向目标赖氨酸残基添加乙酰基和从靶赖氨酸残基去除乙酰基。这些酶的异常活性与许多人类疾病有关，特别是癌症，相当多的HAT和HDAC已被确定为重要的药物靶点。我们的理论方法将集中在Born-Oppenheimer从头计算QM/MM分子动力学模拟，这是一种模拟酶反应的最先进的计算方法，允许对酶活性部位的化学进行准确建模，同时适当地包括蛋白质环境的动力学和影响。具体目标是：1.对HATS的催化机理进行表征，并对tGcn5进行合理的重新设计以提高其效率。目的2：阐明Sirtuins的内部机制，Sirtuins是一个新的O-III类组蛋白脱乙酰基酶家族。目的3：改进从头算QM/MM方法。拟议研究的成功完成将首次提供对帽子和小武器和轻武器的详细的机械理解。这将刺激对这些重要的 酶，并促进基于机制的新型调节剂的开发，用于探测乙酰化依赖的表观遗传途径和用于治疗用途。同时，我们的方法学开发工作将极大地推进模拟酶反应的计算过程，并有助于在这一重要的酶学领域建立与实验方法平等的合作伙伴地位。

DESCRIPTION (provided by applicant): Our long term goal is to develop and apply computational methods to provide novel mechanistic insights into catalysis and regulation of histone modifying enzymes, and to facilitate the rational design of enzyme sub-type specific modulators for probing epigenetic pathways and therapeutic use. Reversible histone acetylation has emerged as a vital regulator in a multitude of essential epigenetic processes. The enzymes responsible for this essential post-translational modification are histone acetyl transferases (HATs) and histone deacetylases (HDACs) that add and remove acetyl groups to and from target lysine residues, respectively. The aberrant activity of these enzymes has been implicated in numerous human diseases, notably cancer, and quite a few HATs and HDACs have been established as important drug targets. Our theoretical approaches will center on Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, a state-of-the-art computational approach to simulate enzyme reactions which allow for accurate modeling of the chemistry at the enzyme active site while properly including dynamics and effects of protein environment. The specific aims are: 1. Characterize the catalytic mechanism for HATs and rational redesign of tGcn5 for its improved efficiency. Aim 2: Elucidate inner workings of sirtuins, a novel family o class III histone deacetylases. Aim 3: Advance ab initio QM/MM methods. The successful completion of the proposed research will provide a detailed mechanistic understanding for HATs and sirtuins for the first time. This will stimulate further mechanistic studies of these important enzymes, and facilitate the development of novel mechanism-based modulators for probing acetylation dependent epigenetic pathways and for therapeutic use. Meanwhile, our methodology development efforts will significantly advance this computational tour de force to simulate enzyme reactions, and help establish it as an equal partner to experimental approaches in this important field of enzymology.